DESCRIPTION: (Applicant's Abstract) Cocaine addiction is a chronic, relapsing disorder for which there is little effective pharmacologic treatment. The preclinical literature suggests that the mesolimbic dopamine system is critically involved in the reinforcing effects of cocaine and in vulnerability to relapse. However, to date relatively little is known about the neurochernical changes in mesolimbic dopamine function in humans and their putative role in mediating cocaine seeking behavior. Recent developments in brain imaging provide the unique opportunity to study these changes and their role in cocaine addiction. During the proposed career development award, the candidate will learn to develop neuroreceptor imaging techniques with PET and to implement these techniques in the study of neurochemical imbalances in chronic cocaine abuse. In addition, the career development period will include training in human behavioral pharmacology, in order to relate brain imaging findings with cocaine taking behavior in humans. Columbia University provides a unique environment to achieve this purpose. The specific aims include the study of pre- and post-synaptic parameters of dopamine transmission in mesolimbic regions (ventral striatum and amygdala) in chronic cocaine users and matched healthy controls. Alterations of dopamine transmission will then be related to laboratory measures of cocaine self-administration following a low dose of cocaine ("priming" dose). Based on preclinical literature, the hypotheses are that low mesolimbic D1 receptor density and high stimulant-induced dopamine release will be correlated with an increased likelihood of cocaine taking behavior in the laboratory. Thus, an unique aspect of this proposal is the combination of state-of-the-art PET technology and established laboratory methods for studying cocaine self-administration. The career development plan proposed in this application is designed both to address these scientific questions as well as to provide the principal investigator an unparalleled training in the neuroimaging and behavioral studies of substance abuse. Toward this aim, a comprehensive educational program including mentoring, didactics, and collaboration with experts in the field has been outlined in this application.